The present invention concerns the diastereoselective synthesis of hydroxyethylene dipeptide isosteres III by a novel route which involves the addition of the amide II to the epoxide I by treatment with strong base at low temperatures, as shown below in Scheme I. ##STR2##
Hydroxyethylene dipeptide isosteres are medicinally important enzyme (renin and HIV protease) inhibitors. In particular, 2 R, 4 S, 5 S diastereomeric hydroxyamide isosteres have been pursued and synthesized as intermediates in the preparation of such enzyme inhibitors, as well as being end-product inhibitors themselves. See, e.g., Vacca, J. P., et al., J. Med. Chem., 34:1228 (1991).
In the past, entry into the the synthesis of hydroxyethylene dipeptide isosteres involved alkylation of a lactone, derived from an aldehyde, DeCamp, A. E., et al., Tetrahedron Lett., 32: 1867 (1991), with various aryl halides to afford the trans-alkylated lactone products. Evans, B. E., et al., J. Org. Chem., 50:4615 (1985); Fray, A. H., et al., J. Org. Chem., 51:4828 (1986).
In the prior art, a four step coupling procedure is necessary to effect amide bond formation from the alkylated lactone for the synthesis of the isosteres of structure III, which is a major problem with this route. The alkylated lactone is saponified to afford an intermediate hydroxy-acid which is then protected at the hydroxyl group to afford the carboxylic acid intermediate. The carboxylic acid intermediate is then coupled with an amine to afford the hydroxy protected isostere which is finally deprotected to afford the isostere III. In addition to being lengthy, the process requires expensive reagents to activate the carboxylic acid, is operationally difficult on a large scale and results in some recovery of the alkylated intermediate lactone after the amide bond formation step. Thus, a new route to the hydroxyethylene dipeptide isosteres that does not involve the lengthy and ineffecient conversion of an alkylated lactone to the desired isostere III would be superior to existing methodology.
The work of Marshall, et al., J. Org. Chem., 50:1602 (1985), has shown that epoxides bearing .alpha.-(metalloalkoxide) groups are much more reactive than the corresponding epoxides bearing .alpha.-ether groups. However, no examples exist of the reaction of epoxides bearing .alpha.-(metallo-amino) or .alpha.-[metallo-(N-t-butoxycarbonyl-amino)] groups with metalated amide enolates.
Experiments involving the reaction of the metalated amide enolate derived from compound II in Scheme I with simple unsubstituted epoxides show that a substantial rate acceleration is gained via epoxide activation by the .alpha.-metalated amino group.
Although metalated chiral amide enolates have been previously used to form 2-alkyl-4-hydroxycarboxamide products by reaction with chiral epoxides [Askin, D., et al., Tetrahedron Lett., 29:4245 (1988)], metalated chiral amide enolates have not previously been used to make hydroxyethylene dipeptide isosteres III by reaction with .alpha.-N-metalated chiral epoxides.
The present invention has several advantages over the prior art for making medicinally important intermediates and end-product compounds useful for the treatment of serious diseases. Most importantly, the novel process of the invention provides a rapid entry into hydroxyethylene dipeptide isosteres by circumventing the problematic four-step coupling/amidation sequence. Thus, the invention is a more economical, operationally practical and efficient process for the construction of hydroxy-ethylene dipeptide isosteres than previous processes. This invention provides a direct, high yielding, stereoselective route to hydroxyamide compounds useful in the preparation of diastereomeric compounds having the ability to inhibit certain proteolytic enzymes, including renin and the protease of human immunodeficiency virus (HIV).